tbuckley/cabot-search huggingface dataset:
Vaccines for immunoprevention of DNA mismatch repair deficient cancers
Authors: Alejandro Hernandez-Sanchez, Mark Grossman, Kevin Yeung, Shizuko S Sei, Steven Lipkin, Matthias Kloor
Journal: Journal for ImmunoTherapy of Cancer (2022)

The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer cells. However, weak immunogenicity and the mutational heterogeneity in many cancers have dampened cancer vaccine successes. With increasing information about mutational landscapes of cancers, mutational neoantigens can be predicted computationally to elicit strong immune responses by CD8 +cytotoxic T cells as major mediators of anticancer immune response. Neoantigens are potentially more robust immunogens and have revived interest in cancer vaccines. Cancers with deficiency in DNA mismatch repair have an exceptionally high mutational burden, including predictable neoantigens. Lynch syndrome is the most common inherited cancer syndrome and is caused by DNA mismatch repair gene mutations. Insertion and deletion mutations in coding microsatellites that occur during DNA replication include tumorigenesis drivers. The induced shift of protein reading frame generates neoantigens that are foreign to the immune system. Mismatch repair-deficient cancers and Lynch syndrome represent a paradigm population for the development of a preventive cancer vaccine, as the mutations induced by mismatch repair deficiency are predictable, resulting in a defined set of frameshift peptide neoantigens. Furthermore, Lynch syndrome mutation carriers constitute an identifiable high-risk population. We discuss the pathogenesis of DNA mismatch repair deficient cancers, in both Lynch syndrome and sporadic microsatellite-unstable cancers. We review evidence for pre-existing immune surveillance, the three mechanisms of immune evasion that occur in cancers and assess the implications of a preventive frameshift peptide neoantigen-based vaccine. We consider both preclinical and clinical experience to date. We discuss the feasibility of a cancer preventive vaccine for Lynch syndrome carriers and review current antigen selection and delivery strategies. Finally, we propose RNA vaccines as having robust potential for immunoprevention of Lynch syndrome cancers.
United States Renal Data System Spotlight on Racial and Ethnic Health Equity: Progress, but Much Remains to Discover, Understand, and Improve
Authors: Kirsten L. Johansen, Neil R. Powe
Journal: Journal of the American Society of Nephrology (2022)

Racial and ethnic inequities in kidney disease in the United States have long been recognized. For example, since the 1980s the United States Renal Data System's (USRDS's) Annual Data Report has consistently demonstrated higher incidence and prevalence of ESKD and lower access to kidney
Association of Extreme Heat and Cardiovascular Mortality in the United States: A County-Level Longitudinal Analysis From 2008 to 2017
Authors: Sameed Ahmed M. Khatana, Rachel M. Werner, Peter W. Groeneveld
Journal: Circulation (2022)

Background: Extreme-heat events are increasing as a result of climate change. Prior studies, typically limited to urban settings, suggest an association between extreme heat and cardiovascular mortality. However, the extent of the burden of cardiovascular deaths associated with extreme heat across the United States and in different age, sex, or race and ethnicity subgroups is unclear. Methods: County-level daily maximum heat index levels for all counties in the contiguous United States in summer months (May–September) and monthly cardiovascular mortality rates for adults ≥20 years of age were obtained. For each county, an extreme-heat day was identified if the maximum heat index was ≥90 °F (32.2 °C) and in the 99th percentile of the maximum heat index in the baseline period (1979–2007) for that day. Spatial empirical Bayes smoothed monthly cardiovascular mortality rates from 2008 to 2017 were the primary outcome. A Poisson fixed-effects regression model was estimated with the monthly number of extreme-heat days as the independent variable of interest. The model included time-fixed effects and time-varying environmental, economic, demographic, and health care–related variables. Results: Across 3108 counties, from 2008 to 2017, each additional extreme-heat day was associated with a 0.12% (95% CI, 0.04%–0.21%; P =0.004) higher monthly cardiovascular mortality rate. Extreme heat was associated with an estimated 5958 (95% CI, 1847–10 069) additional deaths resulting from cardiovascular disease over the study period. In subgroup analyses, extreme heat was associated with a greater relative increase in mortality rates among men compared with women (0.20% [95% CI, 0.07%–0.33%]) and non-Hispanic Black compared with non-Hispanic White adults (0.19% [95% CI, 0.01%–0.37%]). There was a greater absolute increase among elderly adults compared with nonelderly adults (16.6 [95% CI, 14.6–31.8] additional deaths per 10 million individuals per month). Conclusions: Extreme-heat days were associated with higher adult cardiovascular mortality rates in the contiguous United States between 2008 and 2017. This association was heterogeneous among age, sex, race, and ethnicity subgroups. As extreme-heat events increase, the burden of cardiovascular mortality may continue to increase, and the disparities between demographic subgroups may widen.
Biofunctionalized graphene oxide nanosheet for amplifying antitumor therapy: Multimodal high drug encapsulation, prolonged hyperthermal window, and deep-site burst drug release
Authors: Zhen Wang, Hao Cheng, Yu Sheng, Zongkai Chen, Xiaohong Zhu, Jianye Ren, Xiangze Zhang, Lingyu Lv, Huaqing Zhang, Jianping Zhou, Yang Ding
Journal: Biomaterials (2022)
Eliciting anti-cancer immunity by genetically engineered multifunctional exosomes
Authors: Qinqin Cheng, Zhefu Dai, Goar Smbatyan, Alan L. Epstein, Heinz-Josef Lenz, Yong Zhang
Journal: Molecular Therapy (2022)

Exosomes are cell-derived nanovesicles involved in regulating intercellular communications. In contrast to conventional nanomedicines, exosomes are characterized by unique advantages for therapeutic development. Despite their major successes in drug delivery, the full potential of exosomes for immunotherapy remains untapped. Herein we designed genetically engineered exosomes featured with surfaced-displayed antibody targeting groups and immunomodulatory proteins. Through genetic fusions with exosomal membrane proteins, Expi293F cell-derived exosomes were armed with monoclonal antibodies specific for human T-cell CD3 and epidermal growth factor receptor (EGFR) as well as immune checkpoint modulators, programmed death 1 (PD-1) and OX40 ligand (OX40L). The resulting genetically engineered multifunctional immune-modulating exosomes (GEMINI-Exos) can not only redirect and activate T cells toward killing EGFR-positive triple negative breast cancer (TNBC) cells but also elicit robust anti-cancer immunity, giving rise to highly potent inhibition against established TNBC tumors in mice. GEMINI-Exos represent candidate agents for immunotherapy and may offer a general strategy for generating exosome-based immunotherapeutics with desired functions and properties.
Resistance to systemic immune checkpoint inhibition in the peritoneal niche
Authors: Daryl Kai Ann Chia, Yong Xiang Gwee, Raghav Sundar
Journal: Journal for ImmunoTherapy of Cancer (2022)

Immune checkpoint inhibition (ICI) is an established therapeutic option for patients with deficient mismatch repair or high levels of microsatellite instability tumors. Yet, response to ICI among this group is varied, with nearly one-third of patients exhibiting primary resistance. Initial efforts in studying mechanisms of resistance to ICI have focused on intrinsic tumor factors. Host factors such as metastatic niches have unique biological properties that may mediate resistance to ICI but have been less studied date. Patients with metastatic d-MMR/MSI-H gastrointestinal cancers and peritoneal metastases (PM) who had concurrent ascites have been recently shown to have worse outcomes with ICI therapy compared with patients with PM without ascites and patients with non-PM metastases. The juxtaposition of tumors with an intrinsic sensitivity to ICI failing to respond by virtue of the presence of ascites within the peritoneum, brings to the forefront the critical role of the metastatic niche. In this commentary, we discuss mechanisms for ICI resistance that may arise from the immunoprivileged state of the peritoneal cavity, paracrine factors within malignant ascites or tumor-peritoneum interactions. An improved understanding of the peritoneal microenvironment and the use of peritoneal-directed therapies may ameliorate the modest benefit of ICIs in this unique clinical entity.
The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi: a genomic epidemiology study
Authors: Kesia Esther da Silva, Arif Mohammad Tanmoy, Agila Kumari Pragasam, Junaid Iqbal, Mohammad Saiful Islam Sajib, Ankur Mutreja, Balaji Veeraraghavan, Dipesh Tamrakar, Farah Naz Qamar, Gordon Dougan, Isaac Bogoch, Jessica C Seidman, Jivan Shakya, Krista Vaidya, Megan E Carey, Rajeev Shrestha, Seema Irfan, Stephen Baker, Steve P Luby, Yanjia Cao, Zoe Anne Dyson, Denise O Garrett, Jacob John, Gagandeep Kang, Yogesh Hooda, Samir K Saha, Senjuti Saha, Jason R Andrews
Journal: The Lancet Microbe (2022)

The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.Bill & Melinda Gates Foundation.
Developing, validating, updating and judging the impact of prognostic models for respiratory diseases
Authors: Florien S. van Royen, Karel G.M. Moons, Geert-Jan Geersing, Maarten van Smeden
Journal: European Respiratory Journal (2022)

<b>While many prognostic models are developed, few are implemented in clinical practice. A first natural step in prognostic model research is to review and externally validate already existing prognostic models.</b>https://bit.ly/3xrgisU
Chromosome 1q21 aberrations identify ultra <scp>high‐risk</scp> myeloma with prognostic and clinical implications
Authors: Efstathios Kastritis, Magdalini Migkou, Dimitra Dalampira, Maria Gavriatopoulou, Despina Fotiou, Maria Roussou, Nikolaos Kanellias, Ioannis Ntanasis‐Stathopoulos, Panagiotis Malandrakis, Foteini Theodorakakou, Aggeliki Sevastoudi, Evangelos Eleutherakis‐Papaiakovou, Theodora Triantafyllou, Evangelos Terpos, Eirini Katodritou, Meletios A. Dimopoulos
Journal: American Journal of Hematology (2022)

Numerical abnormalities of chromosome 1q (+1q21) are common in patients with newly diagnosed multiple myeloma (MM) but their prognostic impact remains a matter of debate. In addition, the impact of the number of copies of 1q21 is not known. We analyzed 912 consecutive patients with symptomatic MM to evaluate the prognostic implications of +1q21 and of their copy number variations, as assessed by FISH. At the time of initial diagnosis, 249 (27.3%) patients had +1q21, of which 150 (16.4%) had 3 copies and 99 (10.9%) had 4 or more copies. Presence of +1q21 was associated with advanced ISS stage (p = .003), concurrent presence of other cytogenetics aberrations and advanced R-ISS stage (p < .001). Patients with +1q21 had inferior PFS (median 34 vs. 20 months, p < .001) and OS (median 75 vs. 44 months, p < .001) but the copy number of 1q21 had no additional prognostic impact. In multivariate analysis, adjusting for R-ISS, age, treatment and HDM, +1q21 remained an independent prognostic factor both for PFS (p < .001) and OS (p = .008). The detrimental prognostic effect of +1q21 was more profound in R-ISS-3 patients, identifying a subgroup with OS of just 16 months (vs. 46 for R-ISS-3 without +1q21, p < .001). We further validated our findings in an independent cohort of 272 patients. In conclusion, the presence of +1q21 is associated with more advanced disease, inferior PFS, and OS but especially patients with R-ISS-3 disease and +1q21 have a very poor outcome comprising an ultra-high-risk group.
Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease
Authors: Ozge Karayel, Sebastian Virreira Winter, Shalini Padmanabhan, Yuliya I. Kuras, Duc Tung Vu, Idil Tuncali, Kalpana Merchant, Anne-Marie Wills, Clemens R. Scherzer, Matthias Mann
Journal: Cell Reports Medicine (2022)
P1093: A NEW PROGNOSTIC MODEL FOR INDIVIDUAL OUTCOME PREDICTION IN ADVANCED-STAGE HODGKIN LYMPHOMA.
Authors: R. Rask Kragh Jørgensen, S. Eloranta, M. Tang Severinsen, A. Kiesbye Øvlisen, K. Bjøro Smeland, C. Kiserud, J. Haaber Christensen, M. Hutchings, R. Bo-Dahl Sørensen, P. Kamper, I. Glimelius, K. E. Smedby, F. Bergström, T. C. El-Galaly, L. Hjort Jakobsen
Journal: HemaSphere (2022)

Background: Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) are commonly risk stratified based on prognostic scores like the International Prognostic Score (IPS). These scores are often based on dichotomized clinical predictors, leading to loss of information and thus inaccurate prognoses. Aims: This study investigated if a machine learning approach utilizing real world data from aHL patients can outcompete the IPS in predicting overall survival (OS). Methods: This study included patients with classical aHL registered in the Danish Lymphoma Registry (LYFO). We developed a new prognostic model for predicting OS using stacking, which combined several predictive survival models into a single model. The models used in the stacking, were Cox porportional hazard (CPH), Flexible parametric survival (FPS), Random Survival forest and IPS models, with different combinations of covariates included depending on the model. The time-varying area under the curve (AUC), integrated Brier score (IBS), and concordance index (C-Index) were used to measure performance of the new model as well as the IPS and a simplified version containing three risk-factors (IPS-3). The performance measures were computed using 10-fold cross-validation. Results: A total of 1,110 aHL patients were included and the 5-year OS was 81% (95% CI, 79-84%). The IBS for the stacking, IPS, and IPS-3 model was 0.078, 0.099, and 0.096, respectively, while the C-Index was 0.86, 0.73, and 0.71. The time-varying AUC was consistently higher for the stacking-model compared to IPS-models within the first five years after diagnosis (Figure). According to the IPS-model, 143 (12.9%) patients were high-risk (IPS 5-7). The 5-year OS for these patients was 62% (95% CI, 54-71%). We defined an alternative high-risk group by including the 143 patients with the lowest predicted 5-year OS based on the stacking-model. This high-risk group had a 5-year OS of 40% (95% CI, 32-50%). Image:Summary/Conclusion: The new prognostic model for aHL based on machine-learning technique (stacked model) demonstrated a substantial improvement in predictive performance compared to the IPS-models. The model also detected a high-risk group with worse OS than the IPS high-risk group. The model is planned for international validation.
S109: ONCOGENIC DEUBIQUITINATION CONTROLS TYROSINE KINASE SIGNALING AND THERAPY RESPONSE IN ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: P. Ntziachristos, Q. Jin, B. Gutierrez
Journal: HemaSphere (2022)

Background: Dysregulation of kinase signaling pathways via mutations favors tumor cell survival and resistance to therapy and it is common in cancer. Our data unveil how dysregulated deubiquitination controls signaling pathways, leading to cancer cell survival and drug non-response, and suggest novel therapeutic combinations towards targeting T-cell acute lymphoblastic leukemia (T-ALL). Here, we reveal a novel mechanism of post-translational regulation of kinase signaling and nuclear receptor activity via deubiquitination in acute leukemia. Aims: This study aims at 1) characterizing the function of an oncogenic complex composed by two deubiquitinating enzymes in in vitro and in vivo leukemia systems and 2) testing the association of deubiquitinase activity with resistance to therapy in acute lymphoblastic leukemia. Methods: We use genetic mouse and human:mouse xenograft models of T-cell leukemia, biochemical studies (quantitative global proteomics, phosphoproteomics and ubiquitination analysis) and high-throughput molecular biology (chromatin conformation capture (HiC), chromatin accessibility (ATAC-Seq) and gene expression (RNA-Seq)) analyses. Results: We observed that the ubiquitin specific protease 11 (USP11) is highly expressed in lymphoblastic leukemia and associates with poor prognosis in this disease. USP11 ablation inhibits leukemia growth in vitro and in vivo, sparing normal hematopoiesis and thymus development, suggesting that USP11 could be a therapeutic target in leukemia. USP11 forms a complex with USP7 to deubiquitinate the oncogenic lymphocyte cell-specific protein-tyrosine kinase (LCK). Deubiquitination of LCK controls its activity, thereby altering T cell receptor signaling. Impairment of LCK activity leads to increased expression of the glucocorticoid receptor transcript, culminating into transcriptional activation of pro-apoptotic target genes, and sensitizes cells to glucocorticoids in T cell leukemia patient samples. The transcriptional activation of pro-apoptotic target genes, such as BCL2L11, is orchestrated by the deubiquitinase activity and mediated via an increase in enhancer-promoter interaction intensity. Pharmacological inhibition of USP7 or genetic knockout of USP7 in combination treatment of glucocorticoid displayed improved anti-T-ALL efficacy in vivo. Image:Summary/Conclusion: Our data unveil how dysregulated deubiquitination controls signaling pathways, leading to cancer cell survival and drug non-response, and suggest novel therapeutic combinations towards targeting T-cell leukemia.
P1498: INHIBITION OF POLYCOMB REPRESSIVE COMPLEX 2 THROUGH EED INDUCES FETAL HEMOGLOBIN IN HEALTHY AND SICKLE CELL DISEASE MODELS
Authors: B. Stuart, P. Bruno, D. Polioudakis, M. Roth, M. Wertz, A. Edelstein, I. Efremov, D. Matson, J. Dunn
Journal: HemaSphere (2022)

Background: Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations in the hemoglobin β (HBb) gene locus, resulting in dysfunctional or diminished adult hemoglobin (HbA) production that is the root cause of the increased morbidity and mortality associated with these diseases. Individuals with SCD and β-thalassemias who harbor additional genetic alterations that maintain elevated fetal hemoglobin (HbF) expression during adulthood demonstrate improved disease prognosis or, at sufficient HbF amounts, restore normal hemoglobin functions and are asymptomatic. Elucidating the regulatory networks that control HbF expression is critical to the discovery of new therapies for SCD and β-thalassemia. Aims: To elucidate the mechanism by which Polycomb Repressive Complex 2 regulates HbF expression Methods: Genetic and pharmacologic targeting of PRC2 components in healthy and SCD CD34+ derived erythroid cells in vitro and wildtype and Townes HbSS in vivo models. RNA-sequencing was used to look at response to PRC2 modulation and impact on HbF levels. Results: We show that modulation of PRC2 potently downregulates expression of master fetal hemoglobin regulator BCL11A, and thus is a putative upstream regulator of HBG gene expression. Specifically, we demonstrate negative modulation of PRC2 activity via multiple different pharmacologic or genetic knockdown approaches results in decreased expression of BCL11A and concomitant and robust increases in both HBG mRNA and HbF protein in vitro and in vivo. Downregulation of BCL11A is mechanistically distinct from the current standard of care, Hydroxyurea, and pre-clinical HbF induction via FTX-6058 exceeds that observed with Hydroxyurea. Summary/Conclusion: These novel findings further elucidate the regulatory network that underlies fetal hemoglobin gene expression and has important implications for the use of inhibitors of PRC2 as potential therapies for SCD and β-thalassemia. The translation of these findings is underway as FTX-6058, an investigational, novel and potent inhibitor of Embryonic Ectoderm Development (EED), is currently being evaluated in clinical studies as a potential treatment for select hemoglobinopathies (NCT04586985, NCT05169580).